Hematologic Disorders in Pregnancy

Transcript

00:05 --> 00:27Welcome to a series of podcasts brought you by Yale University. This is doctor. Janine Evans associate professor at Yale School of Madison speaking on Lyme disease and the development of a vaccine in the mid 1990s as part of the Yale Peabody Museum's biodiversity and global change day and sponsored by a science Education Partnership Award from the National Institutes of Health.
00:28 --> 00:47Thanks for inviting me the Lyme vaccine story is actually a very interesting one and one of the great things about it was the first description of Lyme arthritis happened in 1975, when some mothers in around the lime area.
00:47 --> 00:52Notice that there was a high incidence of children who were diagnosed with juvenile rheumatoid arthritis.
00:53 --> 00:55And we know that.
00:56 --> 01:20That was way higher than what would have been expected for that patient population so they came down to Yale and engaged Steven Mellowest, a an Allen steer into investigating. It further so it was first described in 1975, an by 1998. We actually had a vaccine that was developed.
01:21 --> 01:51Tried shown to be efficient and put out on the market. So it was a relatively when you think about it short span from start to finish with respect to Lyme disease. I think when you're designing clinical trials. One of the things that are important is what questions do you ask? What is it an important thing to invest time and energy into and what are some of the pitfalls that you can expect and what data do you need to gather?
01:51 --> 02:09So before I get into the exact line vaccine trials. I want to give a little bit of background about some of the Epidemiology and ecology of Lyme disease because they have their very pertinent into what went on in the thinking about the Lyme Vaccine Development.
02:10 --> 02:23So, in the means is a means of background. Lyme disease is really the most common vector borne illness that is reported in the United States and probably accounts for about 90%.
02:24 --> 02:27Or 95% of all reported vector borne illnesses.
02:28 --> 02:43In addition to that it has a very distinct geographic localization within the United States and in areas that are highly endemic up to 1 to 3% of individuals will contract infection from Lyme disease.
02:44 --> 02:51Vector borne means that it's transmitted by.
02:51 --> 03:05A tick or a mosquito or something else that bites. The individual flea all of those sorts of things that then deposit the illness and that's how individuals get it.
03:06 --> 03:39So here are the 3 major areas where people developed Lyme disease. Probably the hyest incidents is along the Eastern Seaboard. From about Massachusetts to Maryland. There's another pocket in Wiscconsin and then a very, very small pocket out in California and again. The reason why the pocket in California is as small as it is, is because how the the tick lifestyle actually is dependent upon feeding on lizards.
03:39 --> 04:11And lizards don't propagate the disease as opposed to Wiscconsin and the East Coast, where probably the biggest animal that is responsible for the perpetuation of Lyme disease is a Brown is the white footed mouse and they carry the Spira Kate with them. Even though they don't themselves get ill. But we also know that Lyme disease occurs worldwide typically in temperate areas, so we've got our pockets, in the United States.
04:11 --> 04:18And then there's also abroad pocket that spans sort of the central part of Europe, all the way to Asia.
04:19 --> 04:51And here's the the ones on the top which is zodia scapularis or the deer. Tick is what's responsible for transmitting Lyme disease underneath that is what's referred to as the Lone Star State tick, which is more common in sort of Texas and southern parts of the United States and then underneath that is the dog tick and these are the various different stages of a ticks life. The eggs odious scapularis ticket has a 2 year lifespan.
04:51 --> 05:03So the first, the first stage is the larval stage, so their hatched, they develop Marvi and the larva feed on animals typically small animals.
05:04 --> 05:23Including the white footed mouse and that's how one that's one stage that the contract, the infection. The next is that they'll after they fed and drop off. They molt or grow up into being a nymphal stage and these are some of the most aggressive.
05:24 --> 05:54Feeders in the ticks lifestyle and these are what the ones who were responsible for transmitting the most cases of Lyme disease because their indiscriminate about who they feed on humans dogs mice? What have you and then they drop off and then the following year. The adults emerge and their preference actually is to feed on deer and they are much, much less likely to transmit Lyme disease than than in full stages are.
05:55 --> 06:12So the principle vectors of eggs odious scapularis, which is detect in the northeast in the Midwest is the IG Zodia Scapula Harris and it's a slightly different tick in the West coast and again their preferences to feed on lizards.
06:13 --> 06:17Although you see this kind of tick in the S for.
06:18 --> 06:24A number of reasons, Lyme disease is not as endemic there as it is in the N.
06:26 --> 06:39And this is the bacteria, which is called a borrelia. That's responsible for causing Lyme disease. So this is what is the infection and it's these little squiggly bacteria?
06:40 --> 06:43That are from a family that's termed borrelia.
06:46 --> 07:01And we know that based on looking at the types of proteins that are present on these bacteria that there's actually 11 different kinds of Borrelia that have been described to date.
07:01 --> 07:20And they've been given various different names, depending on who found them or where they were found, but only three of them to date has been felt to be associated with actually human disease and that includes borrelia sense of strict do.
07:20 --> 07:24Paralia grinny I am brelje absolved and sell side.
07:27 --> 07:43So all of the Lyme disease borrelia that occur in the United States. All are from the census trick. Do class in Europe. You can get all three kinds, but Granny I, an observe see. I actually don't.
07:44 --> 07:46Are present in the United States?
07:46 --> 08:00And the difference between these various different species is that they expressed different proteins on their outside coats and so that can distinct one from another kind.
08:02 --> 08:27And so if you mashed up those borrelia and you ran them out, so that they made different bands depending upon what their weight and size were then you'd get a picture like we see over here, so you see that there's lots. And lots of different proteins that are present on the Borrelia. Some of which the immune system responds to very, very aggressively.
08:30 --> 08:31And.
08:31 --> 09:04Some of the ones that seemed to elicit a very strong immune response are what's termed aspa, which is a protein on the outside outer surface protein a a being that it was described 1st and then B&C and they go DEFG and so forth, then there's one that's called a 41 kilodalton flagellin protein. That's not only its seeing not only in Lyme disease or umbrella.
09:04 --> 09:28But also on lots of other different organisms as well, and then a variety of other ones that have been described and what the researchers did when they found that there's these various different proteins as they actually were capable of being able to isolate them and then clone them so that they could grow up big batches of these various different proteins.
09:29 --> 10:00And what they found was that even within OS pay. There are some variations that take place so that not all aspies are exactly the same OS pay. There's a little bit less of that kind of diversity, then what happens in some of the other proteins such as ASP see where there's lots more of that going on and again. If you're going to use one of these as a vaccine that concern would be if there's lots of diversity.
10:00 --> 10:04You may not be able to be as protective does that make sense.
10:06 --> 10:06OK.
10:07 --> 10:30So the other question is, we've got Lyme disease and it can cause all kinds of problems. As far as illnesses are concerned. Thankfully, the majority of cases of Lyme disease are caught very, very early in the course of the illness and that's the stage of the skin rash and that skin rashes called erythema migrans.
10:31 --> 10:40Other things that can happen and what are things like arthritis that tend to happen months after contracting the illness.
10:41 --> 10:52You can get a facial palsy, which is a drooping of the side of the face certain neurologic things and sometimes it can affect the heart as well.
10:53 --> 11:08Those are much more concerning and the longer that somebody's had an illness the harder. It is to try and get rid of it and sometimes people are left with symptoms following treatment.
11:11 --> 11:38It would be nice to be able to prevent getting the disease in the 1st place. So 1 question is how do we go about protecting ourselves from getting Lyme disease so one thing is to know if the area that you're in has a high rate of Lyme disease, meaning that the ticks in that area carry a lot of disease or the percentage of ticks that carry the disease is high.
11:39 --> 11:47We also know that takes like to hang out and would it in grassy areas. We also know that.
11:49 --> 12:00Although they can occur on lawns usually, it's right on the edge of the lawn in conjunction or right next door bordering on sort of a hoodie, Woody area.
12:00 --> 12:09And we also know that probably the people who are the most at risk for contracting Lyme disease are young children. 'cause they are out and about.
12:10 --> 12:28And the interesting thing is the next and then there's this drop during the teenage in 20 years I guess. Maybe we're not out, doing things in the Woods as much. When were in our teens and 20s and then back up again when in the 30s and 40s, when I guess again people take on these recreational activities.
12:30 --> 13:02So as far as prevention measures are concerned there's a couple of different strategies that people use or have been proposed in order to reduce the incidence of Lyme disease. One would be just don't go there and avoid any areas that have high rates of Lyme disease, which is kind of a bummer because a lot of them are along Cape Cod and Martha's Vineyard and places, that people like to go in vacation. We can try an reduce tick populations as best we can with insecticides.
13:03 --> 13:08And one strategy and very high endemic areas is actually in the early spring when the.
13:08 --> 13:13Than Imps are out to actually then do.
13:13 --> 13:18Do a round of insecticide to try and reduce those populations.
13:19 --> 13:28Another strategy would be to just try and get the deer out because we know they're important to sustain the adults that then.
13:29 --> 13:41You know give rise to the Larva and etc. But to do that. You really would be very hard because you need very, very high fences and it just.
13:42 --> 13:43Would be?
13:43 --> 13:56Very costly in order to do that, you can protect yourself and we'll get into that in a second you can use repellents for ticks and lastly the issue about vaccination, which we're talking about today.
13:58 --> 14:22So here are what's recommended as far as some of the personal protection. Things so make sure that you stay away from going out into the grass and the wilderness stay on the path. They suggest that you wear long sleeve shirts long pants. Tuck your socks in your pants into your socks.
14:22 --> 14:50Wear light colored clothing, so that you can identify ticks. Easilly wear a hat so that they can't get into your hair use repellent, an wear sturdy shoes now you and I both know that in the middle of July. This is a very hard thing to do so, although it's effective. It's not very convenient and people don't like to do it.
14:52 --> 15:10We also know that if people pull ticks off what do you do about that if you found that it actually is a deer tick that you've pulled off they've done a number of studies looking to see whether or not a short course of antibiotics would reduce the risk of developing Lyme disease.
15:11 --> 15:24And we know that even in highly endemic areas. If you pull that kick off within a 24 to 36 hour period your risk of contracting Lyme disease is extremely small so.
15:25 --> 15:493 very large studies really didn't show that the that the risk of having a reaction to the antibiotics outweighed. The fact that you reduce the development of Lyme disease. There was one study that showed if you gave a single course of doxycycline, which is an antibiotic that that actually did a little bit better than doing nothing at all.
15:49 --> 15:57And at this point if you pull a tick off actually getting a blood test to look to see if you have Lyme disease is.
15:58 --> 16:01Is typically negative test? It's not going to help.
16:03 --> 16:03So.
16:04 --> 16:35Is there a need for a vaccine? This is going to require a lot of resources a lot of money into the development. The marketing taking it from you know the observation of whether or not you found something that effective all the way to the point where at the FDA approves it and it's out on the market and this was very controversial through the whole course of the development of the Lyme Vaccine. The people will, who are in favor of it argued that Lyme disease is a major health burden.
16:35 --> 16:49That there's lots of Los work that there's lots of tourist that particularly in endemic areas and estimated that the cost for each case of Lyme disease was about $10,000.
16:49 --> 16:57That, they also argued that the areas that were endemic for Lyme disease we're expanding.
16:58 --> 17:02That some of the late manifestations can be very disabling.
17:03 --> 17:14And that our other means of being able to prevent Lyme disease are not very their inadequate or people just aren't going to do them.
17:14 --> 17:22People who argued against going forward with the Lyme Vaccine said that most cases are diagnosed early.
17:23 --> 17:29When they're diagnosed and treated early people do extraordinarily well so why do we have to do this?
17:30 --> 17:36And that it's it's rarely, if ever fatal.
17:36 --> 17:37So it's not a killer.
17:38 --> 17:49And that there was lots of concerns that potential side effects from the Lyme vaccine would outweigh any benefits that were were found.
17:50 --> 18:14But nonetheless it was moved forward and one of the first things that you try and do is find an animal model that mimics the disease that it is that you're trying to deal with, and so there have been a number of different animals that have that have certain features of human Lyme disease, but not all of them.
18:14 --> 18:47And the one that probably most of the work has been done on have been mice because you know what the genetic background is you know it's easy to be able to measure some of the immunological things and so, if you give certain genetic mice. Lyme disease they will develop and arthritis and the paw on the left hand side is swollen and that's an example of Lyme arthritis and the other thing that they get is actually.
18:47 --> 19:09Heart involvement as well so here we have a mechanism of looking to see whether or not. We can come up with a vaccine to prevent prevent mice from developing Lyme disease and we've got good ways of being able to see whether or not. They've gotten it an again measurement in their blood and from tissue samples.
19:11 --> 19:27So they actually went they purified this outer surface protein a which is one of the proteins on the on the bacteria and they gave it to mice and then they look to see whether or not there was any evidence of Lyme disease.
19:28 --> 19:53And they compared that with what's called the control population where they didn't give them the OS. Pei vaccine and lo and behold, all of the mice who were given the vaccine. None of them developed. Lyme disease as opposed to 100% of their controls were not given the vaccine every single one of them developed Lyme disease.
19:54 --> 19:54And.
19:55 --> 20:02The interesting thing that they observed as well is that if you gave you had to give the vaccine.
20:03 --> 20:19Prior to giving an infection in order to have it be protective if you gave it afterwards. It was absolutely no good. And so it raised the question as to how is this vaccine working in the 1st place?
20:20 --> 20:21And.
20:21 --> 20:26The way vaccines typically work is that you give somebody.
20:27 --> 20:42A protein or whatever against what it is that you're trying to fight and their immune systems develops a defense against it and then they go around doing sort of surveillance and if it comes across that then.
20:43 --> 20:46Tries to get rid of whatever it is the offending Organism is.
20:48 --> 21:00What happens in Lyme disease is that when you give them aspac? How it works? Is it actually as the tickets drinking in the blood containing those antibodies.
21:01 --> 21:11The aspac antibodies wipe out the Borrelia in the stomach of the Tech.
21:12 --> 21:21If you give it afterwards and they've already gotten infected that aspac antibody isn't affective anymore.
21:22 --> 21:27And that mechanism is important to certain issues that came up later.
21:29 --> 21:36So again how this is working is it's wiping it out in the stomach of the tick rather than.
21:37 --> 21:55And so it would be important that you would have very high levels of this around in your body all the time and we also found that there was a certain portion of that. OSP a protein that was responsible for the protection that we saw in the vaccine trials.
21:56 --> 22:15And the reason why it isn't effective after the fact is the fact that what that bacteria does is it is. It makes certain proteins. During various different phases of where it is at the time so when it sinthetix stomach it has it.
22:16 --> 22:25It puts on high levels of this OS. Pei protein the minute that it that it starts to feed and blood comes into the stomach.
22:26 --> 22:32It takes the OS pay off an it ramps up another protein called OSP C.
22:32 --> 22:43So the reason why it's not effective after the fact is that OS pay is no longer being expressed by the bacteria when it's in the human body?
22:44 --> 23:14That makes sense so then we found that it was affective in mice. We found that if you gave it ahead of time that you could protect we found out how it actually worked and then it was time to take it on and see whether or not. It was affective in humans and when you do clinical research, particularly in vaccine trials and many other medications against illnesses as you do it in phases and your very first phase is.
23:14 --> 23:39Is it safe to people tolerate it and what's the appropriate and then Phase 2 is? What's the appropriate dose that you need so the Phase 1 trial, actually took a number of individuals and gave them a spee and just to measure whether or not they their immune system responded to the vaccination and sure enough, at certain levels, it did.
23:40 --> 23:56Then they asked whether what was the optimum dose so they did. Another trial where they did 3 separate dosing amounts and then found out that there was a certain dose 30 micrograms that really gave the best result.
23:57 --> 24:08And then they asked the question well if you've already have Lyme disease and we're giving you this vaccination is it safe in those people and sure enough.
24:08 --> 24:19It was people who had prior history of Lyme disease. It didn't matter. You didn't have a worse reaction. You didn't have a problem with it, and you were able to Mount a response.
24:20 --> 24:43So having done that background work. It was then time to do. The real big massive trials and here there were 2 companies who actually developed a Lyme vaccine and that included Smith Kline Beecham and pasture merrier cannot and both of these companies did major trials and.
24:43 --> 24:57And solicited 10,000 that's a typo. 10,000 people who are volunteers and they either got the 3:00 doses of the vaccine or they got placebo, which was nothing.
24:58 --> 25:09And they gave it to them on a dosing schedule that they had also worked out under previous trials, which was your first dose. Then you got the second dose a month later and then you got the 3rd dose.
25:10 --> 25:1212 months later.
25:12 --> 25:31All the volunteers were given Diaries so that they could capture any kind of side effect that might possibly be experienced and they wanted to know everything again wanting to know whether or not. It was safe and whether or not there were there would be other issues related to the vaccine.
25:33 --> 25:58And then they had to come up with what they decided to be criteria on what made up definite. Lyme disease possible Lyme disease. They also measured to see whether or not somebody could have been infected, but didn't know it, which is called asymptomatic seroconversion and they also did history, physical exams cultures polymerise chain reaction, which is a way of amplifying DNA.
25:59 --> 26:05And they did blood tests looking to see if there was exposure to Lyme disease.
26:06 --> 26:37And what they found was after the first two injections that it was protective about 50% of the time for definite cases and that it protected about 83% of the time from the asymptomatic seroconversion meeting that you've been exposed but you never develop symptoms. But after the 3rd injection that went up to 76% protective about definite cases.
26:37 --> 26:44And 100% protective about from a symptom asymptomatic seroconversion.
26:45 --> 26:47At this point we did not do boosters.
26:47 --> 27:16And similarly I think although it looks a little bit better here. The pasture product. Gay very similar results. These side effect profile. That was associated with the vaccine were common. Typically they were short lived and were pain at the injection site. Sometimes some redness and some soreness similar to when you get a tetanus shot sometimes people develops a low grade fevers fatigue for a couple of days headaches.
27:16 --> 27:47Joint aches and pains, but again, these were usually lasting maybe 1 to 3 days and there was no difference between any serious side effect between the placebo group and the Lyme Vaccine Group and then they look to see whether or not what happens long term. So we got through the 1st year, but is there any lingering potential side effects that might happen and again following people for?
27:48 --> 28:1836 months after that initial trial, there did not appear to be any new issues that developed with relationship to the line vaccine. Then the issue about boosters came up where we know that you need to have high levels of the antibody around and that that drops overtime, so do you need to give a booster? How often do you have to give a booster in order to maintain that high level of antibody to protect individuals?
28:19 --> 28:48The CDC came out with some recommendations on who we ought to consider and again. That's really sort of rooting out who the high risk. Individuals are in order to do that, and the other important thing to remember is the fact that in the original Lyme vaccine. Human trials that was from 18. Two and older so there was a lot of uncertainties was it safe and effective in children.
28:48 --> 28:56And there were actually trials and children that occured afterwards that showed that it was effective and safe as well.
28:56 --> 29:22But at the time that they came out with these recommendations that had not been done So what are some of the controversial issues that also were related to the Lyme vaccine and one is that in other research it was shown that when people developed arthritis in Lyme disease that they may very high titers of ASP antibodies.
29:23 --> 29:50And so the question became if you're going to be giving them are there certain individuals that would be at risk developing arthritis as a result of their vaccination? Was it safe and kids? How often would we need to boost her and remember, we talked about the variability of the proteins from one species to another and if you vaccinate with will protect you against the other types of species as well.
29:52 --> 30:06And lastly since we depend so much upon laboratory confirmation to diagnose Lyme disease. How is that going to impact our ability to be able to?
30:07 --> 30:09To use our blood work effectively.
30:11 --> 30:25And then there was the question about vaccine failures. There were certain individuals that it didn't protect and that it seemed to be in particular, the Pasteur.
30:25 --> 30:56Group that individuals who are over the age of 60 were less likely to have as vigorous and immunological response against the Organism or not so one reason is that you just don't make enough of those aspray antibodies and then there was the question about out in the wild? Is there enough variability going on here that vaccinating with one aspac just wasn't going to cut it and so again this is sort of what happens when you vaccinate.
30:57 --> 31:03This what they're measuring here is actually the protective antibody, which is termed LA 2.
31:04 --> 31:26And what the levels were after each vaccination and then after the 12 months and what you see is you get a pretty decent response after the first two injections and then that subsides an actually drops to a level that is lower than is required for protection and then when you get that 3rd one.
31:27 --> 31:58It brings the levels up even higher and then there's sort of a slower decline that happens. After that, and in those individuals who were were unable to Mount antibody levels above 1300. They were not adequately protected so again. There was a way to be able to measure that and that was going to factor into recommendations as to how often one would need to receive booster shots with respect.
31:58 --> 32:00II wine disease.
32:01 --> 32:09So we took it from the initial description sort of through some of the laboratory.
32:10 --> 32:16Development on to the human trials, some of the issues that were related to the Lyme vaccine.
32:16 --> 32:22And in 1998, the vaccine was approved by the FDA.
32:24 --> 32:27Pasture cannot decided not to go forward with it.
32:28 --> 32:36And Unfortunately due to sort of lack of interest. It was taken off of the market in 2002 because people didn't.
32:37 --> 33:03Feel the need to be to have protection against Lyme disease. So we're back to our wearing are long sleeve shirts and long pants and light colored clothing and tick checks and so forth, but again, I think it's a very interesting story from a variety of different aspects. Despite the fact that it didn't it wasn't sustained.
33:04 --> 33:05Thanks for your attention.
33:11 --> 33:18Doctor Janine Evans is associate professor at Yale School of Madison. This was recorded on April 19th 2007.

Information

Hematologic Disorders in Pregnancy with guest Dr. Kelsey Martin May 19, 2019 Yale Cancer Center visit: http://www.yalecancercenter.org email: canceranswers@yale.edu call: 203-785-4095